Oestratrienes

ABSTRACT

IN WHICH THE DOTTED LINES IN THE POSITIONS 6-7 AND 9-11 INDICATE THE OPTIONAL PRESENCE OF ANOTHER BOND, AND WHEREIN R represents a hydrogen atom, an aliphatic hydrocarbon group having less than 10 carbon atoms, a cycloalkyl group having less than 7 carbon atoms, an aryl group having less than 11 carbon atoms and which may be substituted by a nitro group or by methoxy groups, an adamantyl group, a furyl group or a thienyl group, R1 represents a hydrogen atom or a group OR2, wherein R2 represents a hydrogen atom, an aliphatic hydrocarbon group having less than 4 carbon atoms, a Beta -dimethylaminoethyl group, an acyl residue derived from acetic or sulfuric acid or an alkali metal salt thereof or a 1Htetrazolyl group, and R3 represents a hydrogen atom, a hydroxyl group, an acetoxy group or an oxo group, possess therapeutically useful properties including oestrogenic and hypocholesterolemic activities. New oestratrienes of the formula

United States Patent [191 Marx et al.

[4 1 Sept. 16, 1975 OESTRATRIENES [22] Filed: Apr. 17, 1974 [21] Appl. No.: 461,806

Related US. Application Data [63] Continuation-in-part of Ser. No. 121,582, March 5,

1971, abandoned.

[30] Foreign Application Priority Data Mar. 6, 1970 United Kingdom 10995/70 [52] US. Cl 260/239.55 D; 195/51; 260/2395; 260/239.55 R; 260/397.1; 260/397.45; 260/3975 A; 424/241 3,629,243 12/1971 Marx et al. 260/239.55 D

OTHER PUBLICATIONS Chem. Abstracts, 75: l5l979a.

Primary ExaminerEthel G. Love Attorney, Agent, or Firm-Robert E. Burns; Emmanuel J. Lobato; Bruce L. Adams [57] ABSTRACT New oestratrienes of the formula in which the dotted lines in the positions 6-7 and 9-1 1 indicate the optional presence of another bond, and wherein R represents a hydrogen atom, an aliphatic hydrocarbon group having less than 10 carbon atoms, a cycloalkyl group having less than 7 carbon atoms, an aryl group having less than 1 1 carbon atoms and which may be substituted by :a nitro group or by methoxy groups, an adamantyl group, a furyl group or a thienyl group, R represents a hydrogen atom or a group 0R wherein R represents a hydrogen atom, an aliphatic hydrocarbon group having less than 4 carbon atoms, a B-dimethylaminoethyl group, an acyl residue derived from acetic or sulfuric acid or an alkali metal salt thereof or a lH-tetrazolyl group, and R represents a hydrogen atom, a hydroxyl group, an acetoxy group or an oxo group, possess therapeutically useful properties including oestrogenic and hypocholesterolemic activities.

46 Claims, N0 Drawings '1 OESTRATRIENES RELATED APPLICATIONS This application is a C.I.P. of allowed application Ser. No, 121,582 filed March 1971 and herewith abandoned.

FIELD OF THE INVENTION This invention relates to a new therapeuticallyuseful cestratrienes, to process for their preparation and to pharmaceutical compositions containing them.

THE INVENTION The oestratrienesof the present invention have the general formula: V

in which the dotted lines in the positions 6-7 and 9-1 1 indicate the optional presence of another bond, andv wherein R represents a hydrogen atom, an aliphatic hydrocarbon group having less than carbon atoms, a cycloalkyl group having less than 7 carbon atoms, an aryl group having less than 1 1 carbon atoms and which may be substituted by nitro group or by methoxy groups, an adamanty'l group, a furyl gr'oupor a thienyl group, R, represents a hydrogen atom or a group 0R wherein R represents a hydrogen atom, an aliphatic hydrocarbon group having less than 4 carbon atoms, a

B-dimethylaminoethyl group, an acyl residue derived from acetic or sulfuric acid or an alkali metal salt thereof or a) lH-tetrazoalyl group, and R represents a hydrogen atom, a hydroxyl group, an acetoxy group or an 0x0 group. i

The oestratrienes of the general formula I are therapeutically useful compounds possessing oestrogenic and hypocholesterolemic activities; in some cases there is a favourable ratio between both activities. These compounds can be applied for human as well as veterinary uses; they can be administered orally as well as 'parenterally.

DETAILED DESCRIPTION The oestratrienes of the general formula I may be prepared by methods known for the pre'parationof analogous compounds. The terms methods known per 'se" and in known manner used hereafter refer to methods heretofore used or described'in'chemical literature. The oestratrienes of the general formula I, wherein the 6-7-and 9 1] positions are saturated, R represents the group 0R R is a hydrogen atom and R is as hereinbefore defined, and conform also to the general formula:

can be prepared by decarboxyla tion in known manner of oestratriene-l7B-carboxylic acid of the general formula:

III

wherein R and R are as hereinbefore defined.

This decarboxylation can be carried out, for example, by heating the carboxyliic acid in an organic medium with lead tetraacetate in a nitrogen atmosphere.

Suitable organic solvents are for instance N,N-dimethylforrnamide, N,N-dimethyl acetamide, acetonitrile, 2,4,6-collidine, hexamethyl phosphoric triamide, diethylene glycol dimethyl ether or N-methylZ-pyrrolidon. According to a modification of this process, thedecarboxylation is carried out with a 1404,1701- phenylboryleriedioxy-oestratriene-l7B-carboxylic acid of the general formula:

I wherein R is as hereinbefore defined, and the Ma, l7a-phenylborylenedioxy-oestratriene of the general formula:

b. The 140,17a-dihydroxy-oestratriene of the general formula:

I OH

thus obtained can then be converted into a 1411,1701- (optionally substituted methylene)dioxy-oestratriene of the formula II by reaction with an aldehyde of the formula RCHO, wherein R is as hereinbefore defined.

The reaction with the aldehyde RCHO is preferably carried out at room temperaturein the presence of a strong acid as catalyst, for example perchlon'c, ptoluene sulfonic, sulfuric, hydrochloric acid or phosphorus pentoxide, and if desired in an inert organic solvent, for example a halogenated alkane, methyl acetate,'ethyl acetate, dioxane, tetrahydrofuran, benzene or dimethyl formamide. By the decarboxylation of an oestratriene-l7B-carboxylic acid of the formula III or of a 140:, l 7a-phenylborylenedioxy-oestratriene-17B- carboxylic acid of the formula IV with lead tetraacetate simultaneously a mixture of the corresponding 6aand 6B-acetoxy derivatives of the compounds of the for mulall, respectively of those of the formula V is obtained. g

The oestratriene-l7Bcarboxylic acids of the general formula III are new compounds; some of these acids have been disclosed in our compending U.S. application Ser. No. 856,483 (now US. Pat. No. 3,585,192) and corresponding Belgian Pat. No. 738,668.

The acids of formula 111 can be prepared in 8 reaction steps from the known compound l4a,l7a-dihydroxyprogesterone.

a. First, this compound can be microbiologically hydroxylated in the ll-position, for example with Cunninghamella balesleeana, Curvularia lunata or Asperigillus ochraceus, to give 1 l 1 40:, l 7a-trihydroxyprogesterone.

b. The product of (a) can be dehydrated to the corresponding 9(1l)-dehydro derivative. The llaisomer for example can be acylated with methane sulfonyl chloride, to 11a, 14a, 17atrihydroxyprogesterone-l l-methane sulfonate, which, in a suitable organic solvent, such as dimethylformamide, can then be heated with lithium chloride to give l4a,17a-dihydroxy-9(1l)- dehydroprogesterone. The ll B-isomer, 11B, 140:, l7a-trihydroxyprogesterone, can be reacted with N-bromo-acetamide to give the corresponding 9(1 1 )-dehydro derivative'Preferably, this reaction is carried out at room temperature, in a suitable organic medium, for example pyridine. c. The product of (b) can be dehydrogenated in the 1,2- position, for example by reaction with selenium oxide or 2,3-dichloro4,5-dicyanobenzoquinone, or by fermentation with a suitable microorganism, such as Corynebacterium simplex, to give 1401,1702- dihydroxyl ,9 l l )-bisdehydroprogesterone, that is, l4a,17a-dihydroxy-pregnal ,4,9( l l )-triene- 3,20-dione;

d. This pregnatriene derivative, can then be aromatized, for example by heating it in pyridine or N,N- dimethyl formamide with zinc dust, to give 3,1411,- l7oz-trihydroxy-l9-nor-pregnal,3,5(10),9,(l l

triene-ZO-one.

e. The 9(1 1)-double bond of this compound can then be reduced again, for example catalytically, using platinum oxide or palladium as catalyst, to give 3,1- 4a,l 7a-trihydroxyl 9-norpregna-l ,2,5( )-triene- 20-one and its 9,8-isomer, which compounds can be separated by crystallization or column chromatography.

Each of the isomers can then be reacted further to give respectively the 901- and the 9B-isomer of an oestratrienel7B-carboxylic acid of the formula III.

f. For example, the a-isomer of the product of (e),

i.e. 3 140:,1 7a-trihydroxyl 9-nor-pregnal,3,5( l0)-trien-20-one, can be converted into a corresponding either of the general formula:

VI I

wherein R' represents an aliphatic hydrocarbon group having less than 4 carbon atoms, a B-dimethylaminoethyl group or a 1 H-tetrazoyl group by reaction with an appropriate halogenide of the formula R -hal, or

sulfate of the formula (R SO The reaction is preferably carried out in an organic medium in the presence of an alkaline substance, such as the hydroxide, hydride or carbonate of an alkali metal. The ether of formula VII wherein R represents a methyl group can also be prepared by reaction with diazomethane in a diethyl ether solution.

g. An ether of formula VI] thus obtained can be converted into the corresponding l7B-carboxylic acid by oxidation, for example by means of sodium hypobromite in the presence of the hydroxide of an alkali metal.

h. The product of (g) can then be reacted with an aldehyde of the formula RCHO, wherein R is hereinbefore defined, in the manner described above for the preparation of the l4a,l7a-(substituted methylene)dioxyoestratrienes of the formula II to give an oestratrienel 7B-carboxylic acid of the for- 'mula III. In the same manner, the 9--isomer of the product of (e) can be converted into the corresponding 9B-isomer methylene )dioxy-androstenel 7B-carboxylic acid as starting material. According to this process an androstene- 1 7/3-carboxylic acid of the general formula:

OOH

VIII I Cll-R wherein R is as hereinbefore defined, is first decarboxylated in the same manner as described above for the oestratriene-l7B-carboxylic acids of the formula III and the and rostene derivative of the general formula:

thus obtained is then converted in an oestratriene of the formula II in manner known per se.

This conversion can be carried out in 2 reaction steps:

a. An androstene derivative of the formal IX can be first dehydrogenated in the 1,2-position, for example by reaction with selenium dioxide or by fermentation with a suitable microorganism, such as Corynebacterium simplex. b. The 1,2-dehydr0 derivative thus obtained can then be aromatized, for example by means of naphthyllithium. The reaction is preferably carried out in boiling tetrahydrofuran and in a nitrogen atmosphere. A 3-hydroxy-oestratriene thus obtained can be converted into a corresponding 3-ether of the formula II in the same manner as described above for the preparation of the ethers of the formula VII. 1

According to a modification of this process 1401,1701- phenylborylenedioxy-androst-4en-3-one-17B- carboxylic acid is decarboxylated to 1411,1701- phenylborylenedioxy-androst-4-en-3-one. This compound can then be converted into oestratrienes of the :formula II in manner known per se.

This conversion can be carried out in 4 reaction steps:

a. First, l4a,l7a-dihydroxy-androst4-en-3-one can be hydrolyzed to l401,17a-dihydroxy-androst-4-en- 3-one in the manner described above for the corre sponding oestratrienes of the formula V.

b. In the compound thus obtained a double bond in the 1,2-position can be introduced, for example by fermentation with suitable microorganisms, such as Corynebaclerium simplex.

c. The 1,2-dehydro derivative, i.e. 1401,1701- dihydroxy-androsta-l,4dien-3-one can then be reacted with an aldehyde of the formula RCI-IO, wherein R is as hereinbefore defined, in the manner described above for the corresponding oestratrienes of the formala VI.

d. A l4oz,l7a-(optionally substituted methylene)- dioxy derivative thus obtained can then be aromatized to the corresponding 3-hydroxy-oestratriene and converted into a corresponding 3-ether of the formula II in the same manner as described above. The androstene-17B-carboxylic acids of the formula VIII are also new compounds; some of these have been disclosed in our copending U.S. application Ser. No. 856,467 (nos U.S. Pat. No. 3,585,191) and corresponding Belgian Pat. No. 738,666.

The acids of the formula VIII can be prepared from the known compound 14a,17a,2l-trihydroxyprogesterone. First, this compound can be converted into 14- a, 1 7a-dihydroxy-androst-4-en-3-one-17B-carboxylic acid, for example by means of periodic acid at room temperature in a suitable medium, such as pyridine and water. This compound can then be converted into an androstene-l7,8-carboxylic acid of the formula VIII by reaction with an aldehyde of the formula RCHO, wherein R is as hereinbefore defined, in the manner described above. The compound l4a,l7a-dihydroxyandrost4-en-3-one-l7B-carboxylic acid can also be used to prepare 14oz,l7a-phenylborylenedioxyandrost-4-en-3-one-l7/3carboxylic acid, in the same manner as described above for the preparation of the corresponding oestratriene derivatives of formula IV.

According to another feature of the invention the oestratrienes of the general formula -II can be prepared using the known compound l4ct-hydroxyoestrone as starting material.

This compound can first be: converted into a corresponding 3-ether of the generall formula:

wherein R is as hereinbefore defined. The reaction can be carried out in the same manner as described above for the preparation of the ethers of formula VII.

An oestrone derivative of formula X can be reacted with hydrazine to obtain the corresponding 17- hydrazone derivative. The reaction is preferably carried out in the presence of a catalyst, for example triethyl amine. The hydrazone can then be oxidized, for example with iodine in a mixture of triethyl amine and tetrahydrofuran. The l7-iodo derivative thus obtained can be reduced, for example with sodium in an alkanol, to obtain the corresponding l6-dehydro derivative, that after conversion into the l6a,17a-epoxy derivative, for example with a peracid, can be reduced again, for example with LiAlI-I, to obtain a l4a,l7oz-dihydroxy-oestratriene of the formula VI. A l4a,l7a-dihydroxy-oestratriene thus prepared can then be reacted in the manner described above with an aldehyde of the formula RCHO, wherein R is as hereinbefore defined, to obtain an oestratriene of the general formula II. Ac-

cording to a modification of this process an oestrone derivative of the general formula:

wherein R is as hereinbefore defined, is converted in the manner described above to the corresponding 17ahydroxy-androstene derivative, i.e. 14a, 1 7adihydroxy-androst-4-en-3-one. The conversion of this compound into oestratrienes of formula II has already been described above.

An oestratriene of the general formula ll obtained according to one of these processes can be used to prepare other oestratrienes of the general formulae I or II.

An oestratriene of the formula II, wherein R R can be converted into the corresponding oestratriene of the formula II, wherein R represents a hydrogen atom, by heating it with an alkali metal salt of a lower alkanethiol in a suitable solvent, such as N,N-dimethylformamide.

The same reaction can be carried out with a l4a,l 7- a-dihydroxy-oestratriene of the fonnula VI, wherein R R The compound 3,1401,l7a-trihydroxy-oestral,3,5( lO)-triene thus obtained can then be converted in the manner described above with an aldehyde of the formula RCHO, wherein R is as hereinbefore defined, into an oestratriene of the formula II, wherein R represents a hydrogen atom.

An oestratriene of the formula 11, wherein R represents an acyl residue derived from acetic or sulfuric acid, is preferably prepared by reacting a corresponding 3-hydroxy-oestratriene of the formula II with the appropriate acid chloride or acid anhydride in a suitable medium, for example pyridine.

To prepare an oestratriene of the general formula I, wherein R represents a hydrogen atom, a 3-hydroxyoestratriene of the formula II is first reacted with a chloro-lH-tetrazole or a 2-chloro-l,3-oxazole derivative in a suitable organic medium, for example acetone, under alkaline catalysis. The corresponding 3-ether thus obtained is then reduced to an oestratriene of the formula I, wherein R represents a hydrogen atom, in a hydrogen atmosphere under metal or metal oxide catalysis in a suitable organic solvent. For example, the reaction can be carried out in an ethyl alcohol solution with palladium on coal as catalyst.

An oestratriene of the general formula I, wherein the 9-1 1 position is saturated, can be used to prepare the corresponding 9(] l)-dehydro derivative, for example by reaction with chloranil in a suitable organic solvent, such as t.butanol.

A 6,7-dehydro-oestratriene of the general formula I can be prepared by conversion in manner known per se of the corresponding androstane derivative of the formula lX.

The conversion can be carried out in 3 reaction steps.

a. First, the androstane derivative can be dehydrogenated in the 1,2-position in the manner described above.

b. The 1,2-dehydro derivative thus obtained can then be dehydrogenated in the 6,7-position, for example by reaction with 2,3-dichloro-5,6-dicyanol ,4- benzoquinone in a suitable organic solvent, such as dioxane, under acid catalysis at room temperature. c. The androstal ,4,6-triene derivative thus prepared can then be aromatized to a 6,7-dehydro oestratriene of the formula I by means of naphthyllithium in the manner described above.

The 6-acetoxy derivatives of the oestratrienes of the formula II obtained by the decarboxylation of an oestratrienel 7B-carboxylic acid of the formula III with lead tetraacetate can be hydrolyzed in usual manner to the corresponding 6-hydroxy derivatives of the oestratrienes of the formula II. This reaction can be carried out for example by boiling a 6-acetoxy derivative in dioxane with dilute sodium hydroxide solution.

A 6-hydroxy derivativethus obtained can be converted into the corresponding 6-oxo derivative of an oestratriene of the formula II by oxidation, for example with chromic trioxide in acetic acid.

When the 6-acetoxy derivatives obtained by the decarboxylation of a l4oz,l7a-phenylborylenedioxyoestratriene-17B-carboxylic acid of the formula IV with lead tetraacetate are hydrolyzed in the manner described above, the phenylborylenedioxy group is hydrolyzed simultaneously. A 6-hydroxy derivative of the l4oz,l7a-dihydroxy-oestratrienes of the formula VI thus obtained can be reacted with an aldehyde of the formula RCHO, wherein R is as hereinbefore defined, in the manner described above.

The 6-hydroxy derivatives of the oestratrienes of formula ll thus prepared can then be used again to obtain the corresponding 6-oxo-derivatives.

Among the oestratrienes according to formula I which are prepared by the aforesaid processes are the v following:

3-hydroxy-14a,l7a-methylenedioxy-oestral,3,5( lO)-tri ene.

3-hydroxy- 1 401,1 7a-ethylidenedioxy-oestra- 1,3 ,5( lO)-triene 3-hydroxy- 1 401,1 7a-hexylidenedioxy-oestral,3,5( lO)-triene 3-methoxy- 14a, 1 7a-ethylidenedioxy-oestra- I 1,3 ,5( lO)-triene 3-methoxy-6a, and 6B-acetoxy- 14a, 17aethylidenedioxy-oestral ,3 ,5( l0)-triene 3-methoxy- 1 4a, 1 7a-ethylidenedioxy-9B oestral,3,5(lO)-triene.

3-methoxy- 1 7a-pentylidenedioxy-oestral,3,5( 10)-triene 3-methoxy- 1 4a, 1 7a-hexylidenedioxy-oestral,3,5( l0)-triene 3-methoxy- 14a, 1 7a-benzylidenedioxy-oestral,3,5( lO)-triene 3'-hydroxyl 40:, l 7a-cyclohexylmethylenedioxyoestral ,3 ,5( l())-triene 3-hyd roxy- 1 4a, 1 7or-( 2-methylpropylidene) oestral ,3 ,5( 1O )-triene 3-hydroxy- 1404, l 7a-hexylidenedioxy-oestral,3,5( lO)-triene 3-hydroxy- 1 401,1 7oz-decylidenedioxy-oestral,3,5( lO)-triene 3-methoxy- 1 4a, l 704-( 4 '-nitro-benzylidene )dioxyoestral ,3,5( lO)-triene 3-methoxy- 1 4a, 1 7a-( Z-furfurylidene )dioxy-oestra- 1,3,5, (lO)-triene dioxy- 9 3-methoxy-14oz,170z-(2-thienylmethylene)dioxyoestra-l ,3,5( 1O)-triene 3-methoxy-l4a,17a-,( 1 -naphthylmethylene )dioxyoestra-1,3 ,5( l )-triene 3-methoxy-14a,17a-(3 ',4,5 '-trimethoxybenzylidene )dioxy-oestra- 1 ,3 ,5( 1O )-triene 3-methoxy- 1 4a, 1 7a-( l-adamantylmethylene)dioxyoestral ,3,5( )-triene 3-methoxy14a, 17a-( 2-butenylidene )dioxy-oestral,3,5( l0)-triene 3-hydroxy-14a,l7oz-hexylidenedioxy-oestral,3,5( l0)-triene 3-isopr0pyl ether. 3-hydroxy-1401,17oz-hexylidenedioxy-oestra- 1,3,5( l0)-triene 3-allyl ether 3-hydroxy-14a,l7a-hexylidenedioxy-oestra 1,3,5(10)-triene 3- (B-dimethylaminoethyl) ether 3-hydroxy-14a,17a-hexylidenedioxy-oestra- 1,3,5( l0)-triene 3-acetate sodium 140:, 17a-hexylidenedioxy-oestral ,3,5( 10) triene 3-yl sulfate 3-hydroxyl 40:, l 7a-hexylidenedioxy-oestral,3,5(10)-triene 3- (l-phenyl-1H-Tetraz0lyl)ether 14a, 17a-hexylidenedioxy-oestra-1,3,5( 10)-triene 3-methoxy-14a, l7a-ethylidenedioxy-oestral,3,5(10),9(l l)-tetraene 3-methoxy-6a and 6B-hydroxy-14a, ethylidenedioxy-oestra'l ,3 ,5( l0 )-triene 3-methoxy- 1 4a, l7a-ethylidenedioxy-oestra- 1,3,5( 10)-triene-6-one 3-methoxy-6a and 6a-hydroxy, 140;, hexylidenedioxy-oestra- 1 ,3,5( 10 )-triene 3 -methoxy- 1 4a, l7oz-hexylidenedioxy-oestra- 1,3,5(10),triene-6-one 3-hydroxy- 1 4a,

1,3,5( l0),6-tetraene. The pharmaceutical compositions of the invention comprise at least one oestratriene general formula 1 and a pharmaceutically acceptable carrier or diluent. The compositions may take any of the forms customarily employed for administration of therapeutically active substances, but the preferred types are those suitable for oral administration, especially tablets, including sustained release tablets, pills and capsules, and those suitable for parenteral administration. The tablets and pills may be formulated in the usual manner with one or more pharmaceutically acceptable diluents or excipients, and can include lubricants. Capsules made of adsorbable material, such as gelatin, may contain the active substance alone or in a mixture, with a solid or liquid diluent. Liquid preparations may be in the form of suspensions, emulsions, syrups or elixirs of the active substance in water or other liquid media commonly used for making orally acceptable pharmaceutical formulations.

The active substance may also be made up in a form suitable for parenteral administration, i.e. as a suspension or emulsion in sterile water or an organicliquid 1 7oz-hexylidenedioxy-oestrausually employed for injectable preparations, for example a vegetable oil such as corn or olive oil, or a sterile solution in water or an organic solvent.

For parenteral administration, the daily dosage may be 100 to 250 mg; a suitable concentration for the active compound in an injectable preparation is 100 mg/ml. For oral administration the daily dosage may be 01-500 mg.

A suitable pharmaceutical composition of the invention can be prepared by dissolving 8g of 3-hydroxy- 10 140;, 17oz-hexylidenedioxyoestra-1,3,5( l0)-triene in 11 of purified corn oil and filtering the solution obtained. Soft gelatine capsules are then filled each with 0.25 ml of this solution.

The following Examples illustrate the preparation of the new oestratrienes of the present invention.

EXAMPLE I a. To a solution of 20 g of 14a,17a,2l-trihydroxypregn-4-ene-3,20-dione in a mixture of 300 ml of tetrahydrofuran and 45 ml of water was added a solution of 19.5 g of periodic acid (H 10 in 78 ml of water at such a rate that the addition was completed in about 15 minutes. The mixture was kept at 25C for 2.5 hours; then 280 ml of water were added and the mixture was concentrated in vacuo. The crystals formed were collected, washed with water and dried in vacuo. Yield 17.5 g of 1411,1704- dihydroxy-androst l-en-3-one-17B-carboxylic acid. Melting point: 200c 205C. LR. (in KBr): 11 3320, 2650, 2580, 1725. 1660, 1619 and 1193 cm.

b. A suspension of 200 g of l4a,l7a-dihydroxyandrost-4-en-3-one-173-carboxylic acid in 10 l of methylene chloride, 200 g of paraformaldehyde and 200 ml of percent perchloric acid was thoroughly stirred for half an hour. The organic layer was washed until neutral, concentrated and diluted with 81 of methyl isobutyl ketone. After selective extraction with water at pH 5.95 the methyl isobutyl ketone solution was concentrated. The residue after crystallization from acetone yielded 12.1 g of 14a,1 7a-methylenedioxy-androst-4-en-3-one-17B- carboxylic acid. Melting point: 295.5 5 297C. I.R. (in KBr): u 3425, 2700, 2600, 1722, 1642, 1602, 1161 and 1080 cm". N.M.R. (in CDCL;

some DMSO): 8 0.93, 1.18, 5.03(rboad) and 5.67 ppm.

c. 10 g of 14a,l7a-methylenedioxy-androst-4-en-3- one-17B-carboxylic acid were dissolved in 350 ml of dimethylformamide and during 1 hour nitrogen was bubbled through this solution. The temperature was brought up to 120C and 76 g of lead tatraacetate were added. After half an hour the dimethylformamide was distilled from the reaction mixture and the residue diluted with methyl isobutyl ketone, washed with 5 percent aqueous perchloric acid, concentrated sodium carbonate solution and water until neutral. The solvent was removed by distillation and the residue purified by column chromatography (silicagel, eluent: benzene). After crystallization from acetone 2.9 g of 14a,17amethylenedioxy-androst-4-en-3-one, were obtained. Melting point: 189 191C. LR. (in CHCl v,,,,,,=2780, 1663, 1614, 1162, 1083 and 1018 cm. N.M.R. (in CDCl,,): 8 0.87, 1.20, 4.0(broad), 5.02 (AB-quadruplet) and 5.78 ppm.

(1. ml of a suspension of 2.73 g of l4a,17a-

methylenedioxy-androst-4-en-3-one in water, pre pared by shaking the steroid and water with glassbeads for 16 hours, were added to a fermentation fluid consisting of 15 l of water and containing 0.4 g per liter of formaldehyde and 4 g per liter of a concentrated form of the microorganism Corynebacterium simplex (paste). After 28 hours of fermentation under aeration and stirring at room temperature the fermentation fluid was extracted twice with 6 1 of methyl isobutyl ketone, the organic layer was filtrated and concentrated. The residue after crystallization from acetone yielded 1.87 g of 14a,- 1 7a-methylenedioxy-androsta-1 ,4-dien-3-one.

Melting point: 150 152C. 1.R. (in CHCl 11 1660, 1619, 1600, 1080, and 883 cm. N.M.R. (in CDCl;,): 6 0.87, 1.22, 3.9(broad), 4.95 (AB- quadruplet), 6.12, 6.28 and 7.15 (AB-spectrum) e. A mixture of 2.4 g of naphthalene, 230 mg of lithium metal and 18 ml of anhydrous tetrahydrofuran was boiled for 1.5 hours while a stream of nitrogen was passed through and the mixture was stirred vigorously. After adding 0.2 ml of diphenylmethane and boiling for another 15 minutes there was added a solution of 1.61 g of 14a, 1 7a methylenedioxyandrosta-l ,4-dien-3-one in 24 ml of tetrahydrofuran all at once. Upon stirring and boiling for 0.5 hour the reaction mixture was worked up by adding water; after steam distillation in order to remove naphthalene and extraction with methyl isobutyl ketone the organic layer was washed with water and concentrated. The residue was purified by column chromatography (silicagel, eluent:- benzene) and crystallized from methanol; yield: 0.80 g of 3-hydroxy-l4a,l7amethylenedioxy-oestra-l ,3,5( l)-triene. Melting point: 207 208C. LR. (in CHCl 11 3600, 1607, 1582, 1493, 1161, 1080 and 1019 cm N.M.R. (in CDCl:, some DMSO-D 8 0.78, 3.9(broad), 5.00(AB-quadruplet), 6.56, 6.64 and 7.15 (AB-spectrum) ppm.

EXAMPLE I] a. To a suspension of 10.5 g of 14a,17a-dihydroxyandrost-4-en-3-one-17B-carboxylic acid in 105 ml of dioxane were added 10.5 ml of paraldehyde and 0.1 ml of 70 percent perchloric acid. After 2.5 hours of stirring at room temperature 200 ml of water were added to the reaction mixture and crystals were separated by filtration with suction. After drying there was obtained 10.4 g of pure 14a,17aethylidenedioxyandrost-4-en-3-one-17B carboxylic acid. Melting point: 228 230C. I.R. (in CHC1 11 3435, 1770, 1708, 1664 and 1614 cm'. N.M.R. (in CDCl;, some DMSO-D 8 0.89, 1.22 and 5.68 ppm.

b. According to the procedure described in Example I c) 14a,17a-ethylidenedioxy-androst-4-en-3-0ne- 17B-carboxylic acid was decarboxylated to 1401,17- a-ethylidenedioxy-androst-4-en-3-one. Melting point: 140 142.5C. LR. (in CHCl 11 1665, 1616, 1406 and 1118 cm". N.M.R. (in CDC1 6=0.83, 1.19, 1.28(doublet), 3.9(broad), 5.13 (quadruplet) and 5.78 ppm.

c. According to the procedure described in Example 1 d) 1401,17a-ethylidenedioxy-androst-4-en-3-one was converted into l4a,l7a-ethylidenedioxyandrosta-l ,4-dien-3-one. Melting point: 203 204C. LR. (in CHCl u 1660, 1620, 1602, 1400, 1112 and 889 cm". N.M.R. (in CDC1 8 0.85, 1.22, 1.22(doub1et), 3.9(broad), 5.12 (quadruplet), 6.12, 6.28 and 7.15(AB-spectrum) ppm.

d. According to the procedure described in Example I e) 14a,17a-ethylidenedixoy-androsta-1,4-dien- 3-one was aromatized to 3-hydroxy-l4oz,17aethylidenedioxy-oestra- 1 ,3,5( )-triene. Melting EXAMPLE III 21. According to the procedure described in Example 11 a) 170:-dihydroxy-androst-4-en-3-one-17B- carboxylic acid was converted with hexanal into 14a,1704-hexlidenedioxy-androst-4-en-3-one- 17B- carboxylic acid. Melting point: 176 177C. N.M.R. (in CDCl;,): 8 0.90(triplet), 1.03, 1.22, 5.03(triplet) and 5.83 ppm.

b. According to the procedure described in Example 1c) 14oz, l7a-hexylidenedioxy-androst-4-en-3-one- 17B-carboxylic acid was decarboxylated to 14a,17- a-hexylidenedioxy-androst-4-en-3-one. Melting point: 9l.5 101.5C. LR. (in CHCl 11 1665, 1612 and 1109 cm. N.M.R. (in CDCl;,): 5 0.83, 1.18, 0.89(triplet), 3.93(broad), 4.93 (triplet) and 5.78 ppm.

c. According to the procedure described in Example 1 d) 14a,17a-hexylidenedioxy-androst-4-en-3-one was microbiologically dehydrogenated to l4a,17ahexylidenedioxy-androsta-l ,4-dien-3-one. Melting point: 125.5 126C. LR. (in CHCl 11 1660, 1620, 1600, 1149, 1103 and 885 cm. N.M.R. (in CDCl 5 0.87, 1.23, 3.9(broad), 4.92(triplet), 6.13, 6.30 and 7.l7(AB-spectrum) d. According to the procedure described in Example I e) 14a,17a-hexylidenedioxy-androsta-l,4-dien- 3-one was aromatized to 3-hydroxy-l4a,l7a-

hexylidenedioxy-oestra- 1 ,3,5( 10 )-triene, isolated as an oil. LR. (in CHCI v 3600, 1607, 1581, 1493, 1148 and 1104 cm. N.M.R. (in CDCl 8 0.80, 0.88, 4.0(broad), 5.05(triplet), 6.62, 6.68 and 7.27(AB-spectrum) ppm.

EXAMPLE IV a. 5.5 l of nutrient medium consisting of 0.5 percent of glucose and 0.5 percent of corn steep liquor were inoculated with 275 ml of shake culture of Aspergillus ochraceus. The microorganism was grown at 26C with vigorous stirring and aeration. After 24 hours a solution of 1.4 g of 14a,17oz-dihydroxyprogesterone in 20 ml of dimethylformamide was added. After 72 hours, the conversion being complete, the culture broth was filtered and the filtrate extracted three times with 1 l of methyl isobutyl ketone. The extract was concentrated under reduced pressure and the residue crystallized from methan01: yield: 0.4 g of l 1a,14a,17a-trihydroxyprogesterone. Melting point: 232 234.5C. 1.R. (in

CHCl v,,,,, ,=3608, 3485,1711, 1665, 1612 and b. To a stirred suspension of 5 g of 11a,l4a,17a-

trihydroxyprogesterone in 50 ml of pyridine, 1.2 ml of methane sulfonyl-chloride were added dropwise. The reaction mixture was kept at room temperature for 90 minutes and then poured into 750 ml of water; 5.6 g of l1a,14a,17oz-trihydroxyprogesterone 1 l-methane sulfonate were obtained. Melting point: 161C. LR. (in CHCl v 3600,

3505, 1709, 1665, 1610, 1350, 1333, 1170, 921 and 900 cm'.

. A solution of 5.5 g of lla,14a,17a-trihydroxyprogesterone ll-methane sulfonate and 5.5 g of lithium chloride in 55 ml of dimethylformamide was kept at 100C for 30 minutes. To the cooled reaction mixture 20 ml of water were added; after filtration and drying 3.5 g of l4a,l7a-dihydroxy- 9(11)-dehydroprogesterone were obtained. Melting point: 235 241C. N.M.R. (in CDCl some DMSO-D 8 0.58, 1.34, 2.15, about 4.0, 5.58 and 5.68 ppm. Molecular ion peak in mass spectrum: 344. Calculated for C ,H O 344.

d. A mixture of 10 g of l4a,l7a-dihydroxy-9(1l)- dehydroprogesterone 6.6 g of selenium dioxide, 2 ml of pyridine and 500 ml of t-butanol was refluxed for 17 hours. The precipitated selenium was removed by filtration, the filtrate diluted with 2.5 ml of methyl isobutyl ketone and washed with N sodium hydroxide solution, 0.5 N sulfuric acid and water. The organic fraction was concentrated and the brown, crystalline residue triturated with 50 ml of methanol; 2.0 g of nearly white 1401,1719:- dihydroxy-1,9( 1 l )-bis-dehydroprogesterone were obtained. Melting point: 268 272C. [.R. (in ChC1 u 3605, 3560, 3475, 1710, 1662, 1622, 1602 and 1350 cm.

. A mixture of 1.0 g of l4a,170z-dihydroxy-l,9( l l bisdehydroprogesterone, 30 ml of pyridine containing 0.5 ml of water, and 20 g of zinc dust was heated under reflux with stirring for 210 min. After cooling the zinc dust was removed by filtration and washed with methyl isobutyl ketone. The filtrate was concentrated and the residue dissolved in 25 ml of methyl isobutyl ketone and this solution was washed with N sulfuric acid and water. The solvent was evaporated in vacuo and the residue was crystallized from methanol; yield: 0.50 g of 3,14a,17atrihydroxy-l9-nor'pregnal ,3,5( l),9( l 1)- tetraen-20-one. Melting point: 230 235 C. N.M.R. (in CDCl,, some DMSOD 8 0.68, 2.23, 6.23(broad), 6.55, 6.6 and 7.5(AB- spectrum) ppm.

. A solution of 0.40 g of 3,14a,17a'trihyc1roxy-19-.

nor'pregna-l,3,5(10),9(1l)-tetraen-20-0ne in 15 ml of a mixture 1:1) of methanol and methylene chloride was shaken with 10 mg of platinum oxide for 3 hours in a hydrogen atmosphere. After removal of the catalyst by filtration and concentration of the filtrate there was obtained a residue which was purified by column chromatography (silicagel, eluent: a solution of percent acetone in benzene); yield 120 mg of an a-polar and 160 mg of a polar compound. The a-polar compound proved to be 3,l4o,l7a-trihydroxy-l9-nor-9B- pregna-l ,3,5( )-trien-20-one. Melting point: 167 169C. N.M.R. (in CDCl;, some DMSO-D 5 0.83, 2.21, 6.67, 6.7 and 7.2 (AB-spectrum) ppm. The polar compound proved to be 3,l4a,17- a-trihydroxy-l9-nor-pregna-1,3,5( l0)-trienone (i.e. the 9a-isomer). Melting point: 244 248C. N.M.R. (in CDCl some DMSO-D 8 0.72, 2.23, 6.53, 6.6 and 7.1 (AB-spectrum) ppm.

To a suspension of 10 g of 3,14a,l7a-trihydroxy- 19'n0r-pregna-l,3,5( l0)trien-20-one in 250 ml of chloroform and ml of aqueous potassium hydroxide solution (30 percent) 30 ml of dimethyl sulfate were added dropwise under stirring and after 4.5 hours another portion of 25 ml of KOH and 7.5 ml of dimethyl sulfate was added. After 6 hours of reaction the organic layer was washed with dilute hydrochloric acid, sodium bicarbonate and water respectively and dried for 1 night on potassium carbonate. The solvent was removed by distillation in vacuo and the residue crystallized from a mixture of chloroform and heptane; 6.7 g of 3-methoxy-14a, 1 7a-dihydroxy- 1 9-nor-pregna- 1,3,5( l0)-trien-20-one were obtained. Melting point: 162 163C. LR. (in CHCl u 3610, 3480, 1710, 1605, 1570, 1.490 and 1341 cm N.M.R. (in CDCl;,): 8=0.78, 2.29, 3.80, 6.72, 6.78 and 7.28(AB-spectrum) ppm.

1 g Of 3'methoxy-l4a,17a-dihydroxy-19-norpregna-l,3,5( l0)-trien-20-one was dissolved in 10 ml of dioxane and to this solution 10 ml of a solu' tion of 0.7 rnol sodium hypobromite in 650 ml of 2.5 N sodium hydroxide were added dropwise. The temperature was kept at 25 35C and after 40 minutes of vigorously stirring 7 ml of a solution of 2 mol sodium bisulfite per liter were added until the yellow colour disappeared. The reaction mixture was concentrated in vacuo and to the residue water was added. After extraction with methyl iso butyl ketone the water layer was acidified and again extracted with methyl isobutyl ketone. The solvent was removed by distillation in vacuo and after crystallization of the residue from methanol/- water 0.85 g of 3-methoixy-l4a,l7a-dihydroxyoestra-1,3,5( l0)-triene- 1 7fl' carboxylic acid were obtained. Melting point: 145 147C. 1.R. (in CHCl u 3610, 3400, 2840, 1769, 1710, 1608, 1170 and 1495 cm N.M.R. (in CDCl, some DMSOD 8 0.83, 3.79, 6.68, 6.75 and 7.28 (AB-spectrum) ppm.

i. According to procedure described in Example 11 a) 2.0 g of 3-methoxy-l4a',l7a-dihydroxy-oestra- 1,3,5( l0)-triene-17B-carboxylic acid were converted with paraldehyde into 3-methoxy-l4a,17aethylidenedioxy-oestral ,3,5( 10 )-triene- 1 7B- carboxylic acid (yield 2.0 g). Melting point: 171- 174C. 1.R. (in C110,): 1 3435, 1772, 1710, 1609, 1573, 1498, 1402, 1348 and 1109 cm.

'. According to the procedure described in Example 1 c) 16.0 g of 3-methoxy-l4a,17a'ethy1idenedioxyoestral ,3,5( l0)-triene17/3 carboxylic acid were decarboxylated. After separation by column chromatography (silicagel, eluent: benzene) and crystallization from methanol the following products were obtained: 7.8 g of 3-methoxy-l4a,l7aethylidenedioxy-oestral ,3,5( l0)-triene. Melting point: 124- C. 1.R. (in CHCl v,,,,,,= 1603, 1570, 1493 and 1090 cm. N.M.R. (in CDCI 8 0.80, l.32(doublet), 3.80, 4.0(broad), 5.23 (quadruplet), 6.70, 6.78 and 7.34(AB-spectrum) ppm, and 0.8 g of a mixture of 3-methoxy-6aand 6B-acetoxy- 14a, 1 7oz-ethylidenedioxy-oestra- 1,3,5(10)-triene. 1.R. (in CHCl 11 1720, 1608, 1497, 1399 and 1120 cm. N.M.R. (in CDC1 6 0.80, 0.84, l.32(doublet), 2.08, 2.14, 3.80, 4.0 (broad), 5.l9(quadruplet), 6.1(broad), 6.9(mu1tip1et) and 7.3 (multiplet) ppm.

EXAMPLE V a. According to the procedure described in Example IV g) 10.0 g of 3,l4a,l7a-trihydroxy-l9-nor-9,B- pregna-l,3,5(10)-trien20-one were reacted with dimethyl sulfate in chloroform and water, using sodium hydroxide instead of potassium hydroxide.

280 mg of an oil). I.R. (in CI-ICI 11 2842, 1629, 1602, 1578, 1490, 1399 and i 1115 cm. N.M.R. (in CDCl,,): 8 0.77(doublet), 0.90, 3.76, 3.8(broad), 4,8(quadruplet), 6.55, 6.63 and 7.15(AB-spectrum) ppm.

carboxylic acid (yield 7.4 g). Melting point: 136 137C. I.R. (in CHCl v 3435, 1770, 1710, 1609, 1573, 1498, 1350 and 1109 cm.

b. According to the procedure described in Example The yield was 4.4 g of 3-methoxy-l4a,l7a- 5 I c) 7.4 g of 3methoxy-l4a,l7a-hexylidenedioxyhy y-l r- 1 p g oestra-1,3,5(l0)-triene-l7B-carboxylic acid were Making Point: 1290 133C decarboxylated. After crystallization from me- 3) 3 and thanol/water 4.3 g of 3-methoxy-l4a,l7ap 1 p hexylidenedioxy-oestra-l,3,5()-triene were obb. According to the procedure described in Example 10 i M i i 79 80C i KEY); W g of yy y- 11,, 2832, 1603, 1572, 1493, 1252, 1143 and B-P were 1104 cm- N.M.R. (in CDC1 a 0.78, 0.87, verted into y- 4 y y- B- 3.72, 3.9(broad), 4.93(triplet), 6.55, 6.65 and oestra-l,3,5( l0)-triene-l7,B-carboxylic acid. After 7 18(AB SpeCn-um) purification by selective extraction with a sodium hydroxide solution at pH 6.8 and crystallization EXAMPLE VIII benzene g of 3n lethoxy'l4ail7a' According to the procedure described in Example d1hydroxy-9B-oestra-l,3,5( 10)-t B- II a) 13 g of 3-methoxy-14a,l7a-dihydroxy-oestracarboxyllc acid were obtalned. Meltlng point: 1,3,5( l0) triene l7fi carboxylic acid were com 150 C (dec') (m KBr): 356513455 20 verted with benzaldehyde into 3-methoxy- 2615 2 1610 1572 1487 1260 1243 and 14a,17oz-benzylidenedioxy-oestra-1,3,5(l0)- 1230 triene-l7,B-carboxylic acid (yield 14.4 g). Melting Accordlng to the procedure descrlbed 1n Example Point: 0 1966C LR (in CHCI3): um 3445 II a) 23.5 g of 3-methoxy-l4a,l7a-dihydroxy-9,8- 1770,1710, 1610, 1573, 1495, 1350 and 1095 oestra-1,3,5(l0)-triene-17B-carboxylic acid were cmfl converted pafaldehyde b. According to the procedure described in Example i gf ii igiigg 5 8 1 c) 14 g of 3-methoxy-l4a,l7a-benzylidenedioxyf g g acl yle 6 mg oestra-l,3,5(l0)-triene-l7,B-carboxylic acid were pomt' 3O decarboxylated. After crystallization from med. According to the procedure descrlbed in Example thanol/water 1.5 g of 3-methoxy-l4a,l7a- I c) 4.0 g of 3-methoxy-l4a,17a-ethyl1dened1oxybenzylldenedloxy-oestra-1,3,5( l0)-tr1ene were obacld tained. Melting point: 152- 153C. 1.11. (in 1413; were. decafbmylawd f 7 v,,,,,=3090, 3070, 3035, 2830,1608, 1573, 1495, ethyl1dened1oxy-9B-oestra-l,3,5(l0)-tr1ene (ylel 1250, 1088, 743 and 690 Cmfl' NMR' CDCl;,): 8 0.84, 3.70, 4.1(broad), 5.89, 6.55, 6.63(doublet) and 7.1-7.6(multiplet) ppm.

EXAMPLE IX 40 a. To a solution of 2.1 g of l4oz,l7a-dihydroxyandrost-4-en-3-one-l7B-carboxylic acid in 20 ml of acetone, 0.72 g of phenylboronic acid were added. After 5 minutes the precipitated crystals were filtered and crystallized from benzene; 1.75 g of 1404,1704- phenylloxylenedioxy-androst-4-en-3-onel 78 B- carboxylic acid were obtained. Melting point: 243 244C (dec.) I.R. (in CHCl ):1/,,,,, 3440, 1770, 1710,

136oC l R (in 3 3o 1770 1710 1660, 1610, 1598, 1489, ca. 1320 and 1100 CHI-1.

1608 1572, 1496, and l 102 -i b. According to the procedure described in Example b. According to the procedure described in Example I c) g of l7a'l3henylborylenedioxy EXAMPLE V1 a. According to the procedure described in Example II a) 8 g of 3-methoxy-l4o ,l7a-dihydroxy-oestra- 1,3,5( l0)-triene-l7B-carboxylic acid were converted with n-pentanal into 3-methoxy-14a,l7apentylidenedioxy-oestral ,3 ,5( l0)-trienel 7,8- carboxylic acid (yield 7.5 g). Melting point: 135

I c) 7.5 g of 3-methoxy-l4a,l7a-pentylidenedioxyoestral ,3 ,5( l0)-triene-17B-carboxylic acid were decarboxylated with lead tetraacetate. After crystallization from methanol/water 3.4 g of 3- methoxy- 1 4a, 1 7a-pentylidenedioxy-oestra- 1,3,5( 10)-triene were obtained. Melting point: 71 73C. I.R. (in CHCl 11 2843, 1607, 1573, 1495, 1149 and 1100 cm. N.M.R. (in CDCl 6 0.78, 0.88, 3.72, 3.9(broad), 4.93(triplet), 6.58, 6.63 and 7.l7(AB-spectrum) ppm.

EXAMPLE VII According to the precedure described in Example 11 a) 8 g of 3-methoxy-14a,17a-dihydroxy-oestra- 1,3,5(l0)-triene17B-carboxylic acid were converted with n-hexanal into 3-methoxy-14a,17ahexylidenedioxy-oestra- 1 ,3 ,5 10 )-triene- 1 7B- androst-4-en-3-one-l7B-carboxylic acid were decarboxylated; 5. 8 g of phenylborylenedioxy-ariclrost-4-en-3-one were obtained. Melting point: 248 252C. l.R. (in Cl-ICl ):v,,,,, 1667, 1620, 1602, 1495, 1330, 1105 and 645 cm. 1 16 g of 14a,17a-phenylborylenedioxy-androst-4- en-3-one were dissolved in 28 ml of acetone and 28 ml of aqueous 5 N potassium hydroxide solution. After 30 minutes of boiling the upper layer was separated, concentrated, diluted with benzene and washed until neutral. After evaporation of the solvent the residue was crystallized from heptane and 6 g of 14a,17a-dihydroxy-androst-4-en-3 -one were obtained. Melting point: 209 21 1C. [.R. (in CHCl ):v,, =3615,i35l0, 1665,1615 and 1018 cm".

d. According to the procedure described in Example I d) a suspension of 25 g of 14a,17oz-dihydroxyandrost-4-en-3-one in water was fermented with the microorganism Corynebacterium simplex From the fermentation fluid 18 g of 14a,17adihydroxyandrosta-1,4-dien3-one were isolated. Melting point: 230 232C. I.R. (in CI'ICl ):v,,,,,,= 3609, i 3490, 1660, 1620, 1603 and 890 cm.

. To a suspension of 4.0 g of 14a,l7oz-dihydroxyandrosta-l ,4-dien-3-one in 60 ml of dioxane ml of hexahydrobenzaldehyde and 0.2 ml of 70% perchloric acid were added. After 30 minutes 200 ml of water and dilute sodium hydrogen carbonate so lution were added until neutral. The mixture was extracted with methylene chloride, the exact concentrated and the residue crystallized from acetone. The yield was 4.5 of 1402,1704- cyclohexylmethylenedioXy-androstal ,4-dien- 3-one. Melting point: 225 ,226C. [.R. (in KBr):v,,,,, 3048, 1660, 1622, 1600, 1019 and 882 According to the procedure described in Example I e) 560 mg of 140:, 17acyclohexylmethylenedioxy-androsta-1,4-dien- 3-one were aromatized to 3-hydroxy-14a,17acyclohexylmethylenedioxy-oestra-l ,3,5( 10 triene, isolated as an oil (yield 2.90 mg). I.R. (in KBr):v,,,,,,=- 3350, 3060, 3020, 1610, 1582, 1501 and i 1215 cm. N.M.R. (in CDC] 3X8; 0.81, 3.9(broad), 4.7(broad), 6.53, 6.6 and 7.7 (AB- spectrum) ppm.

EXAMPLE X According to the procedure described in Example IX e) 4 g of 140:,17a-dihydroxy-androsta1,4-dien- 3-one were converted with 2-methylpropanal into 4 g of 14oz,17a-[2-methylpropylidene]dioxyandrosta-l,4-dien-3-one. Melting point: 163 -164C. I.R. (in KBr):v 3045, 1645,1618, 1599, 1089 and 891 cm".

b. According to the procedure described in Example I e) 550 mg of 140:, l7a-[2- methylpropylidene ]dioxy-androstal ,4-dien-3-one were aromatized to 3-hydroxy-14a,17a-[2- methylpropylidene ]dioxy-oestra-1 ,3,5 10 )-,triene, (yield 250 mg). Metlting point: 235 237C. LR- .(in KBr):v,,,,,,= 3422, 3353, 3065, 3024, 1608, 1503, 1215 and 1088 cm. N.M.R. (in CDCl,, DMSO): 8 080, 0.87, 0.98, 3.9(broad), 4.65 (doublet), 6.50, 6.57 and 7.11 (AB-spectrum) EXAMPLE x1 According to the procedure described in Example IX e) 13.6 g of 14a, l7a-dihydroxy-androsta-1,4- dien-3-one were converted with n-hexanal into 165 g of 14a,17a-hexylidenedioxy-androsta-1,4- dien-3-one. Melting point: 125 126C. I.R. (in Cl-ICl ):v,,,,,,=l660, 1620, 1600, 1149, 1103 and 885 cm. N.M.R. (in CDC1 ):8 0.87, 1.23, 3.9( broad), 4.92(triplet), 6.13, 6.30 and 7.17 (AB- spectrum) ppm.

. According to the procedure described in Example I e) 16.5 g of 1401,]7a-hexylidenedioxy-androsta- 1,4-dien-3-one were aromatized to 3-hydroxy- 14a,17a-hexylidenedioxy-oestra-1 ,3 ,5 1 0)-triene, isolated as an 01] (yield 10.6 g). I.R. (in

CHCl ):z/ 3600, 1607,. 1581, 1493, 1148 and 1104 cm". N.M.R. (in CDCl ):8= 0.80, 0.88, 4.0(broad), 5.05(triplet), 6.62, 6.68 and 7.27 (AB- spectrum) ppm.

EXAMPLE x11 ..According to the procedure described in Example IX e) 4 g of l4a,17a-dihydroxy-androsta-l ,4-dien- 3-one were converted with n-decanal into 4.8 g of 14a,17a-decylidenedioxy-androsta-1,4-dien-3-one. Melting point: 108 109C. I.R. (in KBr):v 3046, 1655, 1618, 1599, 1115 and 880 cm.

. According to the procedure described in Example 1 e) 550 mg of 14a,17a,decylidenedioxy-androsta- 1,4dien-3-one were aromatized to 3-hydroxy- 1401,17 a-decylidenedioxy-oestra-l ,3 ,5(10)-t11'ene isolated as an oil (yield 350 mg). I.R. (in KBr):v,,,,, i 3380, 3060, 3020, 1610, 1583, 1500, 1150 and 1110 cm. N.M.R. (in CDCl ):8=0.79, 1.25, 3.9(broad), 4.9(broad), 6.52, 6.60 and 7.13 (AB-spectrum) ppm.

EXAMPLE XIII According to the procedure described in Example IX a) 1 g of 3-methoxy-14a,17a-dihydroxy-oestra- 1 ,3 ,5(10)-triene 17/3-carboxylic acid was converted with phenylboronic acid into 3-methoxy-l4a,17aphenylborylenedioxy-oestra-1,3,5( 10 )-triene- 1 7,8- carboxylic acid (yield 1.1 g). Melting point: 229 230C. I.R. (in CHCl v,,,,, ,=i 3440, 1770, 1709,

1600, 1570, 1492, 1435, 1343, .1319 and 1100 According to the procedure described in Example I c) l g of 3-methoxy- 1 4a, 1 7aphenylborylenedioxy-oestra-1 ,3 ,5( 10)-triene-17B- According to the procedure described in Example IX c) 48 g of 3-methoxy-l4a,l7aphenylborylenedioxy-oestra-1,3,5( 10)-triene were hydrolyzed to 3-methoxy-14a, 1 7a-dihydroxyoestra-l,3,5(10)-triene (yield after crystallization from methanol/water 22.9 g). Melting point: 157 158C. I.R. (in CHCl v 3612, i 3410, 2843, 1608, 1572 and 1492 cm".

According to the procedure described in Example II a) 5 g of 3-methoxy-14o1,17a-dihydroxy-oestra- 1,3,5(lO)-triene were converted with pnitrobenzaldehyde into 3-methoxy-14a,l 701-[4 nitro-benzylidene]dioxy-oestral ,3,5( 1 0 )-triene (yield 5.2 g). Melting point: 151- 152C. I.R. (in KBr):v,,,,, 3120, 3090, 2832, 1605, 1570, 1528, 1493, 1343, 1110 and 1080 cm. N.M.R. (in CDCl )15=O.88, 3.73, 4.1(1broad), 5.97, 6.60, 6z7

and 7.20 (AB-spectrum), 7.63 and 8.13 (AB- spectrum) ppm.

EXAMPLE XIV A mixture of 5 g of 3-methoxy-14a,17a-dihydroxyoestra-1,3,5(10)-triene, 20 ml of dioxane, 10 ml offurfural and 1.8 g of phosphorous pentoxide was stirred for 24 hours at room temperature. After extraction with ethyl acetate the organic layer was washed respectively with dilute sodium hydrogen carbonate solution, a concentrated sodium bisulfite solution (50 percent) and water. The solvent was distilled in vacuo and the residue purified by chromatography on silicagel (eluent: benzene). After crystallization from ethyl acetate/- methanol 3.4 g of 3-methoxy-14a,l7a -[2- furfurylidene]dioxy-oestra-1,3,5( 10)-triene were obtained. Melting point: 143 144C. I.R. (in KBr): v,,,,,,= 3125, 3045, 3015, 2840, 1730, 1610, 1570, 1490, 1255 and 1148 cm. N.M.R. (in CDCI 8 0.83, 3.71, 4.0(broad), 5.93, 6.3(multiplet), 6.53, 6.63 and 7.2 (AB-spectrum), 7.3(multiplet) ppm.

EXAMPLE XV According to the procedure described in Example XIV 4 g of 3-methoxy-14a,17a-dihydroxy-oestral,3,5(10)-triene were converted with thiophene-Z- aldehyde to 3-methoxy-14a,17a-[2- thienylmethyleneldioxy-oestral ,3,5( 10)-triene (yield 3.6 g). Melting point: l57 158C. I.R. (in KBr):v,,,,,,= 3120, 3090, 2832, 1605, 1570, 1528, 2493, 1343, 1253, 1110 and 1080 cm. N.M.R. (in CDC1 8 0.82, 3.70, 4.0(broad), 6.13, 6.55 and 6.67.4 (multiplet) ppm.

EXAMPLE XVI According to the procedure described in Example XIV 4 g of 3-methoxy-l4a, l7a-dihydroxy-oestra- 1,3,5(l)-triene were converted with naphthalene-1- aldehyde to 3-methoxy-l4a,1 7a-[ 1- naphthylmethylene]dioxy-oestra-1,3 ,5 l0)-triene (yield 5.0 g). Melting point: 220 223C. I.R. (in KBr):1/,,,,, 3075, 3068, 3014, 2833, 1609, 1570, 1490, 1255 and 1108 cm. N.M.R. (in CDCl 0.89, 3.75, 4.2(broad), 6.61, 6.7(doublet) and 7.08.2- (multiplet) ppm.

EXAMPLE XVII According to the procedure described in Example XIV 4 g of 3-meth0xy-14a,17a-dihydroxy-oestra- 1,3,5()-triene were converted with 3,4,5-trimethoxy-benzaldehyde to 3-methoxy- 1401,1701-[3 ',4,5 trimethoxy benzylidene]dioxy-oestra-1 ,3,5( l0)-triene (yield 4 g of an oil). I.R. (in CHCl ):v,,,,,,= 2840, 1596, 1496,1460, 1385 and 1128 cm. N.M.R. (in CDCI 8 087, 3.8(multip1et), 4.1(br0ad), 5.87, 6.61, 6.78, 6.70 and 7.23 (AB-spectrum) ppm.

EXAMPLE XVIII According to the procedure described in Example XIV 250 mg of 3-methoxy-14a,17a-dihydroxy-oestral,3,5(10)-triene were converted with adamantane-lcarboxaldehyde to 3-methoxy-14a,l7a-[ 1- adamantylmethylene]dioxy-oestra-1 ,3,5( 10)-triene (yield 115 mg). Melting point: 93 96C. I.R. (in CHCl ):1/,,,,, 1608, 1572, 1493 and 1080 cm". N.M.R. (in CDC1 5 0.80, 1.67, 3.77, 3.9(broad), 4.33, 6.63, 6.70, and 7.25 (AB-spectrum) ppm.

EXAMPLE XIX According to the procedure described in Example II a) 500 mg of 3-methoxy-14oz,17a-dihydroxy-oestra- 1,3,5(10)-triene were converted with crotonaldehyde into 3-methoxy- 1 7a-[ 2-butenylidene]dioxyoestra-l,3,5(l0)-triene (yield 311 mg). Melting point: 92 94C. I.R. (in KBr):E,,,,,,= 1683, 1610, 1574, 1500, 1256, 1150, 1108 and 1038 cm". N.M.R. (in CDCI ):S= 0.80, 1.7l(doublet), 3.73, 3.9(broad), 5.2-6.2 (multiplet), 6.58, 6.65 and 7.20 (AB-spectrum) EXAMPLE xx a. According to the procedure described in Example IV g) 5.5 g of 3,14a-dil1ydroxy-0estra-1,3,5(10)- trien-17-one were converted into 3-methoxy-14ahydroxy-oestra-l,3,5(10)-triene-17-0ne (yield 13.4 g after crystallization from methanol). Melting point: 124 128C. I.R. (in CHCI v =3610, 1740, 1610, 1574, 1495 and 1033 cm.

b. A mixture of 3.5 go of 3-methoxy-l4a-hydroxyoestra-1,3,5(10)-trien-l7-one, 3 ml of hydrazine hydrate and 35 ml of ethyl alcohol was boiled for 2 hours. After dilution with water, filtration and drying of the product 3.6 g of 3-methoxy1l4ahydroxy-oestra-l ,3 ,5(10)-trien-17-one hydrazone were obtained. Melting point 157- 159C. I.R. (in CI-ICl ):v,,, 3608, 3393, 1665, 1609, 1573, 1495 and 1032 cm.

0. To a mixture of 3.3 g of 3-methoxy-14a-hydroxyoestra-1,3,5( 10)-trienl 7-one l7-hydrazone, ml of tetrahydrofuran and 82.5 ml of triethylamine under nitrogen a solution of 5.9 g of iodine in 16.5 ml of tetrahydrofuran was added dropwise. After 30 minutes the solvent was removed by distillation in vacuo and the residue dissolved in methyl isobutyl ketone and washed with respectively dilute hydrochloric acid, water, dilute sodium thiosulfate solution and water. The solvent was removed by distillation in vacuo and the residue crystallized from methanol. 2.9 g of 3-methoxy-14a-hydroxyl7-iodo-oestra 1,3,5(10), 16-tetrane were obtained. Melting point: 164 166C. I.R. (in CHC1 ):v,,,,,,= 3590, 3575, 1608, 1570 and 1494 cm.

d. To a stirred solution of 2.8 g of 3-methoxy-14ozhydroxy-I 7-iodo-oestra-1,3,5( 10),16-tetranene in 164 ml of ethanol, 20 g of sodium (in pieces) were added. After 1% hours boiling the mixture was diluted with water and extracted with methyl isobutyl ketone. The organic layer was washed with dilute hydrochloric acid and water and the solvent was evaporated. After crystallization from methanol 1.3 g of 3-methoxy-l4oz-hydroxy-oestra-1,3,5(10), 16-tetrane were obtained. Melting point: 7884C.

I.R. (in CHCl ):v,, 3570, 1608, 1570, 1494 ande. To a stirred mixture of 960 mg of 3-methoxyl 14ahydroxy-oestra-l,3,5(10),16-tetrane, 960 mg of anhydrous sodium acetate, 4.8 ml of benzene and 4.8 ml of ethyl acetate 3 ml of a solution of mchloro-perbenzoic acid (40% in ethyl acetate) were added dropwise. After 30 minutes the mixture was diluted with ethyl acetate and washed with dilute aqueous potassium carbonate solution and water. The solvent was removed by distillation in vacuo and the residue crystallized from methanol. 630 mg of 3-methoxy-14a-hydroxy-l6a,17aepoxy-oestra-l,3,5(10)-triene were obtained. Melting point: 133 134C. I.R. (in CI-ICl ):v,,,,, 3465, 1608, 1573, 1493 and 1038 cm. N.M.R. (in CDCI 8 0.88, 3.37 and 3.60(AB- spectrum), 3.73 and 6.67.2(multiplet)ppm.

f. To a stirred mixture of 250 mg of lithium aluminum hydride and 7.5 ml of anhydrous ethyl ether a solution of 550 mg of 3-methoxy1l4a-hydroxy- 16a,17a-epoxy-oestra-1,3,5(10)-triene in 12.5 ml of anhydrous tetrahydrofuran was added dropwise and the mixture boiled for 2.5 hours. Excess lithium aluminum hydride was destroyed by the careful addition of methyl isobutyl ketone and then more of this solvent was added to extract the mixture. The organic layer was wahed with 6 N sulfuric acid, dilute potassium carbonate solution and water. After removal of the solvent by distillation in vacuo and crystallization of the residue from methanol 440 mg of 3-methoxy-l4a,l7a-dihydroxyoestra-l,3,5 (10)-triene were obtained. Melting point 158 161C. LR. (in CHCl;,):v,,,,,,= 3612, 3410, 2843, 1608, 1572 and 1492 cm.

g. According to the procedure described in Example IX e) 200 mg of 3-methoxy-14a,17a-dihydroxyoestra-l ,3 ,5(l)-triene were converted with paraldehyde into 3-methoxy-l4a,17a-ethylidenedioxy oestra-l ,3,5()tn'ene (yield after cystallization from methanol 170 mg). Melting point: 128 130C. I.R. (in Cl-lCl ):v 1603, 1570, 1493 and 1090 cm". N.M.R. (in CDCl 8 =0.80, 1.30(d0ublet), 3.75, 3.9(broad), 5.14 (quadruplet), 6.59 and 6.5-7.4(multiplet) ppm.

EXAMPLE XXI A mixture of 1.2 g of 3-hydroxy-14a,l7ahexylidenedioxy-oestra-l ,3 ,5 (10)-triene, ml of hexamethyl phosphoric triamide, 0.9 g of sodium hydride dispersion (50%; in oil) and 2.2 g of isopropyl iodide was stirred for 24 hours at 30C. After dilution with water and extraction with methylene chloride the organic layer was washed with water until neutral. The solvent was evaporated and the residue purified by chromatography on silicagel (eluent: heptane benzene). After crystallization from methanol 670 mg of 3-hydroxy-1404,17a-hexlidenedioxy-oestra-1,3,5(10)- .triene 3-isopropyl ether were obtained. Melting point:

62 65C. I.R. (in CHCl ):v 1602, 1567, 1490, 1380, 1150 and 1108 cm. N.M.R. (in CDCI 6 0.79, 0.87, 1.30(doublet), 3.9(broad), 4.41(quadruplet), 4.92(triplet), 6.57, 6.63 and 7.16 (AB-spectrum) EXAMPLE XXII According to the procedure described in Example XXI 1.5 g of 3-hydroxy-4a,17a-hexylidenedioxyoestra-1,3,5(10)-triene were converted with allyl bro- .mide to 3-hydrosy-14a,17a-hexylidenedioxy-oestra l,3,5(l0)-triene 3-allylether (yield 0.9 g). Melting point: 83 -84C. I.R. (in KBr):1 3012, 1645, 1607, 1569,: 1495, 1250, 1149, 1128 and 1100 cm". N.M.R. (in CDC1 ):6 0.79, 0.87, 3.9(broad), 4.47(multiplet), 493(triplet), 5.l-6.4(multiplet), 6.60, 6.68 and 7.22 (AB-spectrum) ppm.

EXAMPLE XXIII A mixture of 3.7 g of 3-hydroxy-14a,17ahexylidenedioxy-oestra-1,3,5(10)-triene, 3.6 g of sodium hydride dispersion (50 percent; in oil), 50 ml of hexamethyl phosphoric triamide and 5.8 g of 2- dimethylaminoethyl chloride hydrochloride was stirred for 7 hours. After dilution with water the reaction mixture was extracted with methylene chloride and washed with water until neutral. The solution was concentrated and the residue purified by column chromatography on silicagel (elution with benzene, chloroform and methanol); 71 mg of 3-hydrosyl14a,17a-hexylidenedioxyoestra-1,3,5( l0)-triene 3-[ B-dimethylaminoethyl]ether were obtained as an oil. LR. (in CHCl ):1 2780, 1603, 1570, 1492 and 1106 cm". N.M.R. (in CDCI v =0.78, 0.87, 2.35, 3.9(broad),4.03(triplet), 4.9 (broad), 6.57, 6.63 and 7.17 (AB-spectrum) ppm. Molecular ion peak in mass spectrum: 441.Calculated fOI C H NO 2 441.

EXAMPLE XXIV A solution of 100 mg of 3-methoxy-14az,l7aethylidenedioxy-oestra-l,3,5(l0)triene and 200 mg of sodium ethanethiolate in 1.5 ml of N,N-dimethylformamide was boiled for 5 hours. After cooling the mixture was poured out into water, neutralized with dilute hydrochloric acid, the product filtered off and dried; 86 mg of 3-hydroxy-14a,17a-ethyldenedioxy-oestra-l,3,5(10)-triene (iin amorphus form) were obtained. I.R. (in CHCl Vma.1: 3603, 1609, 1585, 1497, 1401, 1126 and 1097 cm- N.M.R. (in CDCl +trace of DMSO-D6):8= 0.80, 1.28(doublet), 3.9(broad), 5.12(doublet), 6.50, 6.57 and 7.08 (AB- spectrum) ppm.

EXAMPLE XXV a. According to the procedure described in Example XXIV 100 mg of 3-methoxy-14a,17a-dihydroxyoestra-l ,3,5(10)-triene were hydrolyzed to 3,1404, 17a-trihydroxy-oestra-1 ,3,5 (10)-triene (yield 25 mg). Melting point: 189 192C. I.R. (in KBr): v,,,,, =3360, 2015, 1603, 1.500 and 1233 cm".

b. According to the procedure described in Example IX e) 20 mg of 3,1404, l7a-trihydroxy-oestra- 1,3,5 10)-triene were converted with paraldehyde to 3-hydroxy-14a,17a-ethylidenedioxy-oestral,3,5(10)-triene (yield 15 mg). The product thus obtained proved to be identical with the end product of Example 11.

EXAMPLE XXVI 5 g of 3-hydroxy-l4a,l7a-hexylidenedioxy-oestra- 1,3,5(10)-triene were dissolved in ml of pyridine and to this solution 4.2 ml of acetyl-chloride were added with vigorous stirring. After 15 minutes the mixture was filtered and the filtrate distributed over water and methylene chloride. The organic layer was washed with N hydrochloric acid and water until neutral. After conventration of the organic layer and purification of the residue by column chromatography 0n silicagel (elution with heptane and carbon tetrachloride) 4.2 g of 3-hydroxy-14a,17a-hexylidenedioxyoestra-l ,3 ,5 1 0)-triene 3-acetate were obtained as an oil. I.R. (in CHCIQ): Vmax 1760,

1745, i 1603, i 1588, 1490, 1149 and 1109 cm- N.M.R. (in CDCl 8 079, 0.87, 2.24, 3.9(broad), 4.9 3 (triplet), 6.72, 6.74 and 7.28 (AB-spectrum) ppm.

EXAMPLE XXVll To 2.4 ml of pyridine 0.9 ml of chlorosulfonic acid were added dropwise at 10C with vigorous stirring and exclusion of moist. A solution of 450 mg of 3- hydroxy-l4a,17a-hexylidenedioXy-oestra-1,3 ,5( 10 triene in 6.6 ml of pyridene was added to the mixture after which the temperature was kept for 10 minutes at 70C. At 35C 45 ml of saturated sodium chloride solution were added with vigorous stirring. The precipitate was filtered and the filtrate extracted with diethyl ether. The solvent was evaporated and the residue dissolved in water. Dilute sodium bicarbonate solution was added until pH 7.1 and the solution was washed with methylene chloride snd extracted with diethyl ether. The ether was removed byy distillation and 280 mg of sodium 1411,17a-hexlidenedioxyoestra-l,3 ,5(10)- triene 3-yl sulfate were obtained as an oil. LR. (in KBr):v 3450, $3060, 1608, 1579, 1492, 1240, 1109 and 1058 cm N.M.R. (in DMSO-D 8 077, 0.83, 3.9(broad),4.9(broad) and 6.8-7.3(multiplet) ppm. Elementary analysis:

Calculated for C H O SNa: C 61.02%; H 6.99%; S 6.78%; Na 4.87%. Found: C 61.57%; H 7.29%; S 5.37%; Na 4.17%.

EXAMPLE XXVII.

A mixture of 2.0 g of 3-hydroxy-14a,17a-hexlidenedioxy-oestra-1,3 ,5 (IO-triene, 1.1 g of 1-phenyl5- chloro-lH-tetrazole, 1.5 g of potassium carbonate and 50 ml of acetone was boiled with stirring for 16 hours. After extraction with methyl isobutyl ketone the organic layer was washed with brine until neutral and concentrated in vacuo. After crystallization from methanol 2.0 g of 3-hydroxy-14a,17a-hexylidenedioxyoestra-l ,3 ,5 1 0)-triene 3 -[1-phenyl-1l-ltetrazolyl]eth er were obtained. Melting point: 88 -89C. LR. (in KBr): 11 3075 3060, 1590, i 1535, 1500, 1485, 759 and 680 cm. N.M.R. (in CDCl ):8 =0.80, 0.87, 3.9(broad), 4.94(triplet) and 6.97.9- (multiplet) ppm.

EXAMPLE XXIX A solution of 1.0 g of 3-hydroxy-14a,l7ahexylidenedioxy-oestra- 1 ,3,5( 10)-triene 3-8 l-phenyl- 11-l-tetrazoly1]ether in 35 ml of benzene was kept in an hydrogen atmosphere in the presence of 100 mg of palladium-catalyst (10 percent palladium on coal, moistr. ened with water) at a temperature of 45C with stirring for 60 hours. During this period another portions of 100 mg of catalyst were regularly added. After filtration over dicalite some methyl isobutyl ketone was added to the filtrate and the resulting solution concentrated. The residue was crystallized from methanol; yield: 590 mg of 14a,17a-hexylidenedioxy-oestra- 1,3,5()-triene. Melting point: 112 113C. LR. (in KBr):11,,,,, 3100, 3075, 3063, 3030, 3018, 1598, 1482,1143, 1102 and 736 cm- .N.M.R. (in CDC1 8 080, 0.88, 3.9(broad), 4.9(broad) and 6.8-7.6 (multiple) ppm.

EXAMPLE XXX A mixture of 1 g of 3-methoxy-14a,17aethylidenedioxy-oestra-l ,4,5(10)-triene, 15 ml of dioxane, 60 ml of t-butanol and 4 g of chloranil was boiled for 23 hours with stirring in a nitrogen atmosphere. After filtration and concentration of the filtrate the residue was dissolved in methylene chloride and washed respectively with dilute sodium hydroxide solution, dilute hydrochloric acid and with N sodium hydrogen carbonate solution and water untill neutral. After removal of the solvent by distillation the residue was purified by column chromatography on silicagel (eluent: benzene). After crystallization from methanol/ water 200 mg of 3-methoxy-14a,17a-ethylidenedioxy-oestra- 1,3,5(10),9, (11)-tetraene were obtained. Melting point: 116C. 1.R. (in KBr): 11 3090, 3030, 2835, 1632, 1604, 1569, 1492, 1396, 1250 and 115 cm. N.M.R. (in CDC1 ):6 0.78, 1.24(doublet), 3.75, 3.9(broad), 5.10(quadruplet), 6.2(broad), 6.57, 6.6 and 7.54(AB-spectrum) ppm.

EXAMPLE XXXI a. Through a mixture of 15.0 g of 1401,1701- hexylidenedioxy-androsta-1 ,4-dien-3-one, 600 ml of dioxane (pure) and 10 g of 2,3-dichloro-5.6- dicyano-1,4'benzoquinone a stream of hydrogenchloride was passed until the concentration was 1.25 mole HCl per liter. After 19 hours of stirring with exclusion of moisture at room temperature dilute sodium hydroxide solution was added until neutral. The mixture was stirred with acidified alumina in benzene and upon filtration and concentration of the filtrate a residue was obtained which was purified by column chromatography in silicagel (eluent: benzene). After crystallization from methanol 2.0 g of 14a, 17ahexylidenedioxyandrosta-1 ,4,6-trien-3were obtained. Melting point: 112 113C. LR. (in KBr):v,, 3038, 1642, 1620, 1599, 1571, and 1103 cm.

b. According to the procedure described in Example I e) 550 mg of 14a,17a-hexlidenedioxy-androsta- 1,4,6-trien-3-one were aromatized to 3-hydroxy- 14a,17a-hexylidenedioxy-oestra-1,3 ,5 (10),6- tetrane, isolated as an oil (yield 51 mg). LR. (in KBr):v,,,,,,= L 3340, 3030, 1615, 1575, 1492 and 1108 cm. N.M.R. (in DrCcl )zv =0.80, 0.87, 3.9(broad), 5.0(broad), 5.5(broad), 5.95 and 6.4(AB-spectrum), 6.53, 6.59 and 7.1(AB- spectrum) ppm.

EXAMPLE XXXII 790 mg Of the mixture of 3-methoxy-6a and 6,8- acetoXy-14a, 17a-ethylidenedioxy-oestra-1 ,3 ,5(10)- triene obtained in Example IV j), 8 m1 of dioxane and 3 m1 of aqueous 2 N potassium hydroxide solution were boiled for 2 hours. The mixture was neutralized with dilute hydrochloric acid and the dioxane was removed by distillation in vacuo. The crystalline residue was filtered and washed with water. After drying 640 mg of a mixture of 3-methoxy-6a and 6,8-hydroxy-14a,l7a-

ethylidenedioxy-oestra-l ,3,5( 10)-triene were obtained. 1.R. (in CHcl 11 =3605,1608,1578,1491, 1400 and 1120 cm'. N.M.R. (in CD0 8 0.82, 1.30(doublet), 3,67, 3.77, 3.9(broad), 4.7(broad), 5.l3(quadruplet) and 6.67.4(multiplet) ppm.

EXAMPLE XXXlll 620 mg Of the mixture of 3-methoxy-6oz and 6B- hydroxy-14a,17a-ethylidenedioxy-oestra-1,3 ,5( 10 triene obtained in Example XXXII, were dissolved in 9 ml of chromic trioxyde reagent (prepared by adding 300 mg of chromic trioxyde to 1 ml of water and 9 ml of acetic acid). After 45 minutes of stirring the mixture was neutralized with dilute sodium hydroxide solution and extracted with methyl isobutyl ketone. The organic layer was washed with dilute sodium hydroxide solution and water until neutral and concentrated. After crystallization of the residue from methanol/water 330 mg of 3-methoxy- 1 4a, 1 7a-ethylidenedioxy-oestra-l ,3,5( 10 trien-6-one were obtained. Melting point: 100 103C. l.R. (in KBr): 11 3085, 3065, 3040, 2842, 1678, 1605, 1565, 1490, 1398, 1245 and 1120 cm. N.M.R. (in CDCl 6 0.82, l.3l(doublet), 3.82, 3.9(broad), 5.l4(quadruplet), 7.27, 7. ll and 7.50 (AB-spectrum) ppm.

EXAMPLE XXXlV a. According to the procedure described in Example 1X c) the mixture of 3-methoxy-6a and 6B- acetoxy-14a, 1 7a-phenylborylenedioxy-oestral,3,5( lO)-triene obtained in Example Xlll b), was

hydrolyzed to a mixture of 3-methoxy-6a and 63,1- 401,17a-trihydroxy-oestra-l,3,5(l)-triene. l.R. (in CHCl 11 3602, 3490, 2838, 1608, 1570, 1490 and 1032 cm. N.M.R. (in CDCl 8=0.81, 3.2(broad), 3.75, 3.9(broad), 4.8(broad), 6.85 and 6.6-7.4(multiplet) ppm.

b. According to the procedure described in Example IX e) 3 g of the mixture of 3methoxy-6a and 6,8,1 4a, 1 7a-trihydroxy-oestra-l ,3 ,5( 10 )-triene were converted with nhexanal into a mixture of 3- methoxy-a I and 6,8-hydroxy, 14a,17a hexylidenedioxy-oestral ,3,5( l0)-triene (yield 2.2 g). LR. (in KBr): 11 3350, 3090, 3065, 3035, 1610, 1572, 1495, 1239, i 1105 and 1040 cm". N.M.R. (in CDCl;,): 8 0.80, 0.87, 3.77,

3.9(broad), 4.7(multiplet), 4.9(multiplet), 6.87,

6.8 and-7.2 (AB-spectrum) ppm.

EXAMPLE XXXV According to the procedure described in Example XXXIII 2.2 g of the mixture of 3-methoxy-6a and 6,8- hydroxy-14a,l7a-hexylidenedioxy-oestra-l,3,5( 10)- A triene obtained in Example XXXIV, were oxidized to 3-methoxy- 1 404,1 7a-hexylidenedioxy-oestra- 1,3,5(l0)-trien-6-one (yield 1.4 g of an oil). [.R. (in CHCl 11 1680, 1607, 1565, 1492, 1104 and 1034 cm". N.M.R. (in CDCl 8 0.82, 0.87, 3.83, 4.0(broad), 4.96(triplet), 7.29 and 6.9-7.6(multiplet) What we claim as new and desire to secure by letters patent is:

1. An oestratriene of the formula in which the dotted lines in the positions 6-7 and 9-1 1 indicate the optional presence of another bond, and wherein R represents a hydrogen atom, an aliphatic hydrocarbon group having less than 10 carbon atoms, a cycloalkyl group having less than 7 carbon atoms, an aryl group having less than 11 carbon atoms and which may be substituted by a nitro group or by methoxy groups, an adamantyl group, a furyl group or a thienyl group,

R represents a hydrogen atom or an 0R group,

wherein R represents a hydrogen atom, an aliphatic hydrocarbon group having less than 4 carbon atoms, a fl-dimethylaminoethyl group, an acyl residue derived from acetic or sulfuric acid or an alkali metal salt thereof or a lH-tetrazolyl group, and

R represents a hydrogen atom, a hydroxyl group, an

acetoxy group or an oxo group.

2. An oestratriene according to claim 1, wherein the 6-7 and 9-1l positions are saturated, R represents the group CR and R is a hydrogen atom.

3. An oestratriene according to claim 2 wherein R represents a hydrogen atom or a methyl group.

4. An oestratriene according to claim 2, wherein R represents an aliphatic hydrocarbon group having 3 carbon atoms or a fl-dirnethylaminoethyl group.

5. An oestratriene according to claim 2, wherein R represents an acyl residue derived from acetic or sulfuric acid or an alkali metal salt thereof or a ll-l-tetrazolyl group.

6. An oestratriene according to claim 1, wherein R represents a'hydrogen atom.

7. An oestratriene according to claim 1, wherein R represents a hydroxyl group, an acetoxy group or an oxo group. l

8. An oestratriene according to claim 1, wherein R represents a hydrogenatom or an aliphatic hydrocarbon group having less than 10 carbon atoms.

9. An oestratriene according to claim 1, wherein R represents an aryl group having less than 11 carbon atoms and which may be substituted by a nitro group or by methoxy groups.

10. An oestratriene according to claim 1, wherein R represents the cyclohexyl, an adamantyl, a fury] or a thienyl group.

11. An oestratriene according to claim 1 which is 3- hydroxy-l404,17a-methylenedioxy-oestral ,3 ,5( l0 triene.

12. An oestratriene according to claim 1 which is 3- hydroxyl4a,17a-ethylidenedioxy-oestra-l ,3,5( 10 triene.

13. An oestratriene according to claim 1 which is 3- hydroxy-14a,l7oz-hexylidenedioxy-oestra-l ,3 ,5( l0 triene.

14. An oestratriene according to claim 1 which is 3- methoxy-14a,l7a-ethylidenedioxy-oestra-1 ,3 ,5 l0 triene.

15. An oestratriene according to claim 1 which is 3- methoxy-6aand 6B-acetoxy-l4oz,l7a-ethylidene dioxy-oestra-l ,3 ,5( l0 )-triene.

16. An oestratriene according to claim 1 which is 3- methoxy-14oz, 17oz-ethyliclenedioxy-9B-oestral,3,5( lO)-triene.

17. An oestratriene according to claim 1 which is 3- methoxy- 14a,17a-pentylidenedioXy-oestral ,3,5( 10)- triene.

18. An oestratriene according to claim 1 which is 3- methoxy-14a,l7a-hexylidenedioxy-oestra-l ,3 ,5( l

triene.

19. An oestratriene according to claim 1 which is 3- methoxy- 1 4a, 1 7a-benzylidenedioxy-oestral ,3 ,5( l0 triene.

20. An oestratriene according to claim 1 which is 3- hydroxy- 1 4a, 1 7a-cyclohexylmethylenedioxy-oestral,3,5(lO)-triene.

21. An oestratriene according to claim 1 which is 3- hydroxy- 1 401,1 7a-( 2-methylpropylidene )dioxy-oestra- 1,3,5( l0)-triene.

22. An oestratriene according to claim 1 which is 3- hydroxy-l411,17a-decylidenedioxy-oestra-l ,3 ,5( triene.

23. An oestratriene according to claim 1 which is 3- methoxy- 14oz,l 7a-( 4'nitro-benzylidene)dioxy-oestral,3,5( l0)-triene.

24. An oestratriene according to claim 1 which is 3- methoxy-14oz,17a-(Z-furfurylidene)dioxy-oestral,3,5(10)-triene.

25. An oestratriene according to claim 1 which is 3- methoxy-14a,l7a-(2-thienylmethylene)dioxy-oestral,3,5( lO)-triene.

26. An oestratriene according to claim 1 which is 3- methoxy-l 4a,17a-( l-naphthylmethylene )dioxyoestra-l ,3,5( l0)-triene.

27. An oestratriene according to claim 1 which is 3- methoxy- 1 401,1 7a-( 3 ',4',5 '-trimethoxybenzylidene)dioxy-oestra-1,3,5( 10)-triene.

28. An oestratriene according to claim 1 which is 3- methoxy-l4a,17a-( l-adamantylmethylene )dioxyoestra-1,3,5( l0)-triene.

29. An oestratriene according to claim 1 which is 3- methoxy- 1 4a, 1 7a-( 2-butenylidene )dioxy-oestra- 1,3,5( 10)-triene.

30. An oestratriene according to claim 1 which is 3- hydroxy-l4a,l7a-hexylidenedioxy-oestra-1,3 ,5( 10)- triene 3-isopropy1 ether.

31. An oestratriene according to claim 1 which is 3- hydroxy-l 411,1 7a-hexylidenedioxy-oestra-l ,3 ,5( 10)- triene 3-allyl ether.

32. An oestratriene according to claim 1 which is 3- hydroxy-l4a,17a-hexylidenedioxy-oestra-1,3 ,5( l0 triene 3-( ,B-dimethylaminoethyl)ether.

33. An oestratriene according to claim 1 which is 3- hydroxy-l4a,17a-hexylidenedioxy-oestra-1,3 ,5( 1O triene 3-acetate.

34. An oestratriene according to claim 1 which is sodium 14a,17a-hexylidenedioxy-oestra-1,3 ,5( l0 triene 3-yl sulfate.

35. An oestratriene according to claim 1 which is 3- hydroxy- 1 4a, 1 7a-hexylidenedioxy-oestra-l ,3 ,5( l0 triene 3-( l-phenyll H-tetrazolyl)ether.

36. An oestratriene according to claim 1 which is 14- a,17a-hexy]idenedioxy-oestra-1,3 ,5( l0 )-triene.

37. An oestratriene according to claim 1 which is 3- methoxyl4a,l7a-ethylidenedioxy-oestra- 1,3 ,5( l0),

9( 1 1)'-tetraene.

38. An oestratriene according to claim 1 which is 3- hydroxy-l4a,17a-hexylidenedioxy-oestra-l,3 ,5 l0),6-

tetraene.

39. An oestratriene according to claim 1 which is 3- methoxy-6a and 6fi-hydroxy- 14a, 1 7aethylidenedioxy-oestra- 1 ,3,5( lO)-triene.

wherein R and R are as defined in claim 1'.

44. Process for the preparation of an oestratriene as defined in claim 1 which comprises decarboxylating an 1404, l 7a-phenylborylenedioxy-oestratriene- 1 7,8- carboxylic acid of the formula:

wherein R is as defined in claim 1, hydrolysing a 14a,- l7a-phenylborylenedioxy-oestratriene of the formula:

thus obtained, and reacting a l4a,l7oz-dihydroxyoestratriene of the formula:

thus obtained, with an aldehyde of the formula RCHO, wherein R is as defined in claim 1.

45. Process for the preparation of an oestratriene as defined in claim 1 which comprises decarboxylating an androstene-l7B-carboxylic acid of the formula:

COOH

wherein R is as defined in claim 1, dehydrogenating in the 1,2-position an androstene derivative of the formula:

thus obtained, aromatising an androsta-l,4-dien-3 one of the formula:

thus obtained, and optionally converting a 3-hydroxyoestratriene of the formula:

thus obtained with a compound selected from the group consisting of a halogenide of the formula R -hal and a sulfate of the formula (R SO wherein R represents an aliphatic hydrocarbon group having less than 4 carbon atoms, a B-dimethylaminaethyl group or a 1H-tetrazolyl group, to a corresponding 3-ether of the formula:

46. Process for the preparation of an oestratriene as defined in claim 1 which comprises converting 14ahydroxy-oestrone with a compound selected from the group consisting of a halogenide of the formula R -ha1 and a sulphate of the formula (R S0 wherein R is as defined in claim 45, to a corresponding. 3-ether of the formula:

reacting a compound thus obtained with hydrazine to obtain a corresponding l7-hydrazone derivative of the formula:

OH R 0 oxidizing a l7-hydrazone compound thus obtained with iodine to a corresponding l7-iodo derivative, reducing this compound with sodium and an alkanol to a corresponding 16-dehydro derivative of the formula:

OH I R 0 converting a l6-dehydro derivative thus obtained with a peracid to a corresponding l6a,l7a-epoxy derivative, reducing this compound by means of LiAlH to a 14a,l7a-dihydroxy-oestratriene of the fonnula: 

1. AN OESTRATRIENE OF THE FROMULA
 2. An oestratriene according to claim 1, wherein the 6-7 and 9-11 positions are saturated, R1 represents the group OR2 and R3 is a hydrogen atom.
 3. An oestratriene according to claim 2 wherein R2 represents a hydrogen atom or a methyl group.
 4. An oestratriene according to claim 2, wherein R2 represents an aliphatic hydrocarbon group having 3 carbon atoms or a Beta -dimethylaminoethyl group.
 5. An oestratriene according to claim 2, wherein R2 represents an acyl residue derived from acetic or sulfuric acid or an alkali metal salt thereof or a 1H-tetrazolyl group.
 6. An oestratriene according to claim 1, wherein R1 represents a hydrogen atom.
 7. An oestratriene according to claim 1, wherein R3 represents a hydroxyl group, an acetoxy group or an oxo group.
 8. An oestratriene according to claim 1, wherein R represents a hydrogen atom or an aliphatic hydrocarbon group having less than 10 carbon atoms.
 9. An oestratriene according to claim 1, wherein R represents an aryl group having less than 11 carbon atoms and which may be substituted by a nitro group or by methoxy groups.
 10. An oestratriene according to claim 1, wherein R represents the cyclohexyl, an adamantyl, a furyl or a thienyl group.
 11. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -methylenedioxy-oestra-1,3,5(10)-triene.
 12. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -ethylidenedioxy-oestra-1,3,5(10)-triene.
 13. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-triene.
 14. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -ethylidenedioxy-oestra-1,3,5(10)-triene.
 15. An oestratriene according to claim 1 which is 3-methoxy-6 Alpha - and 6 Beta -acetoxy-14 Alpha ,17 Alpha -ethylidene dioxy-oestra-1,3,5(10)-triene.
 16. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -ethylidenedioxy-9 Beta -oestra-1,3,5(10)-triene.
 17. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -pentylidenedioxy-oestra-1,3,5(10)-triene.
 18. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-triene.
 19. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -benzylideNedioxy-oestra-1,3,5(10)-triene.
 20. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -cyclohexylmethylenedioxy-oestra-1,3,5(10)-triene.
 21. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -(2-methylpropylidene)dioxy-oestra-1,3,5(10)-triene.
 22. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -decylidenedioxy-oestra-1,3,5(10)-triene.
 23. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -(4''nitro-benzylidene)dioxy-oestra-1,3,5(10)-triene.
 24. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -(2-furfurylidene)dioxy-oestra-1,3,5(10)-triene.
 25. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -(2-thienylmethylene)dioxy-oestra-1,3,5(10)-triene.
 26. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -(1-naphthylmethylene)dioxy-oestra-1,3,5(10)-triene.
 27. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -(3'',4'',5''-trimethoxy-benzylidene)dioxy-oestra-1, 3,5(10)-triene.
 28. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -(1-adamantylmethylene)dioxy-oestra-1,3,5(10)-triene.
 29. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -(2-butenylidene)dioxy-oestra-1,3,5(10)-triene.
 30. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-triene 3-isopropyl ether.
 31. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-triene 3-allyl ether.
 32. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-triene 3-( Beta -dimethylaminoethyl)ether.
 33. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-triene 3-acetate.
 34. An oestratriene according to claim 1 which is sodium 14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-triene 3-yl sulfate.
 35. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-triene 3-(1-phenyl-1H-tetrazolyl)ether.
 36. An oestratriene according to claim 1 which is 14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-triene.
 37. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -ethylidenedioxy-oestra-1,3,5(10), 9(11)-tetraene.
 38. An oestratriene according to claim 1 which is 3-hydroxy-14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10),6-tetraene.
 39. An oestratriene according to claim 1 which is 3-methoxy-6 Alpha and 6 Beta -hydroxy-14 Alpha ,17 Alpha -ethylidenedioxy-oestra-1,3,5(10)-triene.
 40. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -ethylidenedioxy-oestra-1,3,5(10-trien-6-one.
 41. An oestratriene according to claim 1 which is 3-methoxy-6 Alpha and 6 Beta -hydroxy,14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-triene.
 42. An oestratriene according to claim 1 which is 3-methoxy-14 Alpha ,17 Alpha -hexylidenedioxy-oestra-1,3,5(10)-trien-6-one.
 43. Process for the preparation of an oestratriene as defined in claim 1 which comprises decarboxylating an oestratriene-17 Beta -carboxylic acid of the formula:
 44. Process for the preparation of an oestratriene as deFined in claim 1 which comprises decarboxylating an 14 Alpha ,17 Alpha -phenylborylenedioxy-oestratriene-17 Beta -carboxylic acid of the formula:
 45. Process for the preparation of an oestratriene as defined in claim 1 which comprises decarboxylating an androstene-17 Beta -carboxylic acid of the formula:
 46. PROCESS FOR THE PREPARATION OF ANOESTRATRIENE AS DEFINED IN CLAIM 1 WHICH COMPRISES CONVERTING 14A-HYDROXY-OESTRONE WITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OF HALOGENIDE OF THE FORMULA R2''-HAL AND A SULPHATE OF THE FORMULA (R2'')2 SO4, WHEREIN R2'' IS AS DEFINED IN CLAIM 45, TO A CORRESPONDING 3-ETHER OF THE FORMULA: 